Bioinformatic identification of key candidate genes and pathways in axon regeneration after spinal cord injury in zebrafish

Zebrafish and human genomes are highly homologous;however,despite this genomic similarity,adult zebrafish can achieve neuronal proliferation,regeneration and functional restoration within 6–8 weeks after spinal cord injury,whereas humans cannot.To analyze differentially expressed zebrafish genes between axon-regenerated neurons and axon-non-regenerated neurons after spinal cord injury,and to explore the key genes and pathways of axonal regeneration after spinal cord injury,microarray GSE56842 was analyzed using the online tool,GEO2R,in the Gene Expression Omnibus database.Gene ontology and protein-protein interaction networks were used to analyze the identified differentially expressed genes.Finally,we screened for genes and pathways that may play a role in spinal cord injury repair in zebrafish and mammals.A total of 636 differentially expressed genes were obtained,including 255 up-regulated and 381 down-regulated differentially expressed genes in axon-regenerated neurons.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment results were also obtained.A protein-protein interaction network contained 480 node genes and 1976 node connections.We also obtained the 10 hub genes with the highest correlation and the two modules with the highest score.The results showed that spectrin may promote axonal regeneration after spinal cord injury in zebrafish.Transforming growth factor beta signaling may inhibit repair after spinal cord injury in zebrafish.Focal adhesion or tight junctions may play an important role in the migration and proliferation of some cells,such as Schwann cells or neural progenitor cells,after spinal cord injury in zebrafish.Bioinformatic analysis identified key candidate genes and pathways in axonal regeneration after spinal cord injury in zebrafish,providing targets for treatment of spinal cord injury in mammals.     

The NEDD4-1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma

E3 ubiquitin ligases primarily determine the substrate specificity of the ubiquitin-proteasome system and play an essential role in the resistance to bortezomib in multiple myeloma (MM). Neural precursor cell-expressed developmentally downregulated gene 4-1 (NEDD4-1, also known as NEDD4) is a founding member of the NEDD4 family of E3 ligases and is involved in the proliferation, migration, invasion and drug sensitivity of cancer cells. In the present study, we investigated the role of NEDD4-1 in MM cells and explored its underlying mechanism. Clinically, low NEDD4-1 expression has been linked to poor prognosis in patients with MM. Functionally, NEDD4-1 knockdown (KD) resulted in bortezomib resistance in MM cells in vitro and in vivo. The overexpression (OE) of NEDD4-1, but not an enzyme-dead NEDD4-1-C867S mutant, had the opposite effect. Furthermore, the overexpression of NEDD4-1 in NEDD4-1 KD cells resensitized the cells to bortezomib in an add-back rescue experiment. Mechanistically, pAkt-Ser473 levels and Akt signaling were elevated and decreased by NEDD4-1 KD and OE, respectively. NEDD4-1 ubiquitinated Akt and targeted pAkt-Ser473 for proteasomal degradation. More importantly, the NEDD4-1 KD-induced upregulation of Akt expression sensitized MM cells to growth inhibition after treatment with an Akt inhibitor. Collectively, our results suggest that high NEDD4-1 levels may be a potential new therapeutic target in MM.     

CT引导徒手腔内联合插植自适应后装与传统A点后装治疗宫颈癌剂量比较

目的 探讨CT引导徒手腔内联合插植实现影像引导自适应后装(IGABT)相较于传统A点二维后装(CP)剂量学优势,明确其在宫颈癌治疗中的价值。方法 选取在中山大学肿瘤医院行全量放疗的宫颈癌患者 26例,每例患者行4次后装治疗。治疗时先徒手置入宫腔管及2根插植针,后增加插植针数量并调整方向、深度,分别行CT扫描获得2套图像。勾画高危临床靶区(HRCTV),A点和危及器官(直肠、膀胱及乙状结肠)。在2套图像上分别行CP和IGABT计划设计,并配对t检验、Wilcoxon检验两者剂量参数差异。结果 以CP计划的覆盖指数(CI)进行分组,A组(CI≥0.90)包含20个CP和对应IGABT计划,B组(CI<0.90)包含84个CP和对应IGABT计划。A组的HRCTV体积及肿瘤直径明显小于B组(46.7cm³∶62.1cm³,P<0.001及3.1cm∶4.4cm,P<0.0001)。IGABT显著提高所有及B组D90%及覆盖指数,降低膀胱剂量,减少A组乙状结肠剂量,并改善剂量适形度及均匀性。结论 IGABT能提高靶区覆盖、剂量适形度和均匀性,保护危及器官,且对肿瘤较大的患者仍有优势。     

The Comprehensive Analysis of Efficacy and Safety of CalliSpheres^® Drug-Eluting Beads Transarterial Chemoembolization in 367 Liver Cancer Patients: A Multiple-Center,Cohort Study

This study aimed to investigate the efficacy, safety, and prognostic factors of drug-eluting beads transarterial chemoembolization (DEB-TACE) in treating Chinese patients with liver cancer. A total of 367 liver cancer patients from 24 medical centers were consecutively enrolled in this multiple-center, prospective cohort study, including 275 hepatocellular carcinoma (HCC) cases, 37 intrahepatic cholangiocarcinoma (ICC) cases, and 55 secondary liver cancer cases. All the patients received CalliSpheres^® DEB-TACE treatment. Treatment response, overall survival (OS), change of liver function, and adverse events (AEs) were assessed. DEB-TACE treatment achieved 19.9% complete response (CR) and 79.6% objective response rate (ORR), with mean OS of 384 days [95% confidence interval (CI): 375–393 days]. CR and ORR were both higher in HCC patients compared with primary ICC patients and secondary liver cancer patients, while no difference was discovered in OS. Portal vein invasion was an independent risk factor for CR, while portal vein invasion, previous conventional TACE (cTACE) treatment, and abnormal blood creatinine (BCr) were independent risk factors for ORR. In addition, largest nodule size 5.0 cm, abnormal albumin (ALB), and abnormal total bilirubin (TBIL) independently correlated with unfavorable OS. Most liver function indexes were recovered to baseline levels at 1–3 months after DEB-TACE. Common AEs were pain, fever, vomiting, and nausea; most of them were at mild grade. CalliSpheres^® DEB-TACE is efficient and well tolerated in Chinese liver cancer patients. Portal vein invasion, previous cTACE treatment, largest nodule size, abnormal BCr, ALB, and TBIL correlate with worse prognosis independently.     

Comparative pharmacokinetics and tissue distribution of cryptotanshinone,tanshinone IIA,dihydrotanshinone I,and tanshinone I after oral administration of pure tanshinones and liposoluble extract of Salvia miltiorrhiza to rats

Salvia miltiorrhiza is one of the most commonly used traditional Chinese medicines in the treatment of cardiovascular and cerebrovascular diseases. Cryptotanshinone (CTS), tanshinone IIA (Tan IIA), dihydrotanshinone I (diTan I), and tanshinone I (Tan I) are the main active compounds in the liposoluble extract of Salvia miltiorrhiza. The differences in the pharmacokinetic and tissue distribution behaviors of the four tanshinones after oral administration of the liposoluble extract of Salvia miltiorrhiza and pure compounds are not clear. This study aims to compare the pharmacokinetics and tissue distribution of the four tanshinones after oral administration of pure tanshinone monomers and the liposoluble extract of Salvia miltiorrhiza. An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) analysis method was developed for the determination of the four tanshinones. The results showed that the AUC and C_max of tanshinones in rats receiving the extract of Salvia miltiorrhiza were significantly increased compared with those receiving the pure tanshinones. In the tissue distribution experiments, the AUC of the four tanshinones in the extract was much greater than the AUC of the monomers in the lung, heart, kidney, liver, and brain, and the coexisting constituents particularly promoted the distribution of tanshinones into tissues that the drug cannot sufficiently penetrate. These findings suggested that the coexisting constituents in the liposoluble extract of Salvia miltiorrhiza play an important role in the alteration of plasma concentration and tissue distribution of the four tanshinones. Understanding these differences could be of significance for the development and application of Salvia miltiorrhiza extract and tanshinone components.     

纤维蛋白原/白蛋白比值比对可手术乳腺癌患者预后的影响

目的探讨纤维蛋白原/白蛋白比值比(FAR)对可手术乳腺癌患者预后的影响。 方法依据纳入、排除标准，收集中国医学科学院北京协和医院2013年1～12月收治的520例Ⅰ～Ⅲ期可手术乳腺癌患者临床资料进行回顾性研究。在术前检测血浆纤维蛋白原和白蛋白水平。将纤维蛋白原与白蛋白质量浓度比值乘以100定义为FAR。根据受试者工作特征曲线确定FAR最佳临界值，并依据最佳临界值将受试者分为高FAR组(FAR>6.99)147例和低FAR组(FAR≤6.99)343例。采用Kaplan-Meier法和log-rank检验评估2组患者的DFS和OS，用Cox比例风险回归模型分析患者DFS和OS的影响因素。 结果log-rank检验显示，高FAR组患者的DFS和OS均比低FAR组差(χ²＝32.885、16.320，P均<0.001)。Cox比例风险回归模型单因素分析和多因素分析均显示：高FAR为患者DFS的独立危险因素(HR＝4.092，95%CI：2.425～6.903，P<0.001；HR＝4.226，95%CI：2.476～7.212，P<0.001);高FAR为患者OS的独立危险因素(HR＝3.907，95%CI：1.913～7.978，P<0.001；HR＝4.320，95%CI：2.087～8.942，P<0.001)。 结论术前高FAR患者的无疾病进展时间更短，OS率更低。术前FAR水平有望成为预测乳腺癌患者预后的有效指标。     

Therapeutic effect of mesenchymal stem cell on Hashimoto’s thyroiditis in a rat model by modulating Th17/Treg cell balance

Abstract

The autoimmune condition Hashimoto’s thyroiditis (HT) is a disease wherein lymphocytes mediate the autoimmune damage and destruction of the thyroid gland. There are currently no effective means of treating HT, with the primary strategies of thyroid hormone therapy, surgery, or immunomodulatory therapy being associated with serious risks and side effects. There is thus a clear and urgent need to identify novel treatments for HT. In this study, we utilize female SD rats induced HT to evaluated the ability of transplanted MSCs to regulate Th17/Treg interactions in a rat Hashimoto’s thyroiditis (HT) model system. The results showed that Rats in the HT model group exhibited increased thyroid autoantibody levels consistent with successful model development, whereas these levels were lower in rats treated with MSCs. There were also fewer thyroid lesions and less lymphoid infiltration of the thyroid in MSC-treated rats relative to HT model rats, as well as fewer Th17 cells and more Treg cells – an observation consistent with the cytokine analyses. All of these showed that MSCs can regulate Th17/Treg interactions in a rat Hashimoto’s thyroiditis (HT) model system. It suggested that transplanted MSCs could be a potential immunotherapy strategy for the treatment of Hashimoto’s thyroiditis.     

治疗性腹腔镜胃癌腹主动脉旁淋巴结清扫术的操作技巧及临床意义

目的探讨治疗性腹腔镜胃癌腹主动脉旁淋巴结清扫术的安全性和有效性。方法回顾性分析2017年1月至2018年12月就诊广东省中医院胃肠外科实施治疗性腹腔镜胃癌腹主动脉旁淋巴结术的6例病人基线资料、术中及术后短期结果。结果6例病人术前经影像学评估均存在第16组淋巴结转移,无其他远处转移,经转化治疗后,均达到部分缓解并顺利完成腹腔镜胃癌D2根治并腹主动脉旁淋巴结清扫术,术中1例因合并胰腺侵犯而联合行胰体尾+脾切除术,无中转开腹、腹腔出血、脏器损伤等并发症发生;中位手术时长482.5(445,510)min;中位淋巴结清扫总数、腹主动脉旁淋巴结(para-aortic lymph nodes,PALN)清扫总数及PALN阳性数目分别为50(16,80)枚、18(3,31)枚、3.5(0,15)枚,其中5例PALN病理阳性,1例阴性;术后1例出现胰瘘,1例胸腔积液,1例腹泻,Clavien-Dindo分级均为2级,经对症治疗后均好转出院;术后中位住院时间17(6,30)天,术后30天内无二次手术及死亡发生;中位随访时间13.25(10~18)月,3例病人因肿瘤复发死亡,术后存活时间10~18月,余3例均未见肿瘤复发转移。结论治疗性腹腔镜腹主动脉旁淋巴结清扫术在技术上是可行的,对于胃癌合并PALN转移的患者。     

Apatinib as an alternative therapy for advanced hepatocellular carcinoma

Angiogenesis plays an important role in the occurrence and development of tumors. Registered tyrosine kinase inhibitors targeting vascular endothelial growth factor reduce angiogenesis. Apatinib, a tyrosine kinase inhibitor, can specifically inhibit vascular endothelial growth factor receptor 2, showing encouraging anti-tumor effects in a variety of tumors including advanced hepatocellular carcinoma(HCC). This article intends to review the clinical research and application prospects of apatinib in the field of HCC.